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Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin.

Syndecan-4 保护心脏免受凝血酶切割的骨桥蛋白的促纤维化作用。

  • 影响因子:4.44
  • DOI:10.1161/JAHA.119.013518
  • 作者列表:"Herum KM","Romaine A","Wang A","Melleby AO","Strand ME","Pacheco J","Braathen B","Dunér P","Tønnessen T","Lunde IG","Sjaastad I","Brakebusch C","McCulloch AD","Gomez MF","Carlson CR","Christensen G
  • 发表时间:2020-02-04
Abstract

:Background Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin. Methods and Results Osteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions Thrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.

摘要

: 背景心脏压力超负荷发生在高血压或瓣膜狭窄患者中,由于活化的心脏成纤维细胞过度产生细胞外基质而诱导心脏纤维化。这最初为心脏提供了必要的机械支持,但最终会损害功能。骨桥蛋白与纤维化相关; 然而,潜在的信号机制还不是很清楚。在此,我们研究了凝血酶切割的骨桥蛋白对心脏纤维化的影响,并探讨了 syndecan-4 在调节骨桥蛋白切割中的作用。方法和结果在主动脉缩窄小鼠压力超负荷心脏中,骨桥蛋白被凝血酶上调和切割。与血液心脏停搏液相比,接受晶体液的主动脉瓣狭窄患者血浆中裂解的骨桥蛋白较高,可能是因为肝素诱导的凝血酶抑制较少。裂解的骨桥蛋白和凝血酶裂解后暴露的特异性骨桥蛋白肽序列 RGDSLAYGLR 均诱导心脏成纤维细胞产生胶原。与骨桥蛋白一样,主动脉缩窄后硫酸乙酰肝素蛋白多糖 syndecan-4 上调。与骨桥蛋白裂解位点的硫酸乙酰肝素结合域一致,发现 syndecan-4 与左心室和心脏成纤维细胞中的骨桥蛋白结合,并保护骨桥蛋白免受凝血酶的裂解。Syndecan-4 细胞外部分的脱落在后期重塑阶段更为突出,此时分裂的骨桥蛋白水平增加。结论凝血酶切割的骨桥蛋白可诱导心脏成纤维细胞产生胶原。Syndecan-4 可保护骨桥蛋白免受凝血酶的裂解,但在重塑的后期,当 syndecan-4 脱落时,这种保护作用就会丧失,有助于心脏纤维化的进展。

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